Sepiadarium austrinum, the southern bottletail squid, is a small squid that inhabits sediments along Australia’s south-east coast. When provoked, it rapidly secretes large volumes of slime, and field observations suggest that this is toxic to crabs. This study provides the first proteomic analysis of a slime secretion from a cephalopod and the first investigation of a member of the family Sepiadariidae using proteomic methods. The proteomic composition of this slime was analyzed using a combination of tandem mass spectrometry and transcriptomics and found that it was remarkably complex with 1735 identified protein groups (FDR: 0.01). Of these, 15 were identified as putative toxins including three short (80-130AA) cysteine rich secreted proteins with no homology to proteins on the NCBI or UniProt databases. Our S. austrinum protein database of 40,475 proteins was created from the transcriptome by combining predictions from TransDecoder software with an additional 84 novel proteins identified by proteogenomics. This last step proved crucial for the identification of toxin-like proteins with the most abundant protein in slime (also toxin-like) being identified through this method. Our study highlights the importance of proteomics in toxin discovery by using direct proteomic measurement within a toxic secretion (slime) rather than its parent gland.